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99mTc-Hydrazinonicotinic acid-cyclo[γ-d-Glu-Ala-Tyr-d-Lys]-Trp-Met-Phe-NH2

, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: March 25, 2010.

Chemical name:99mTc-Hydrazinonicotinic acid-cyclo[γ-d-Glu-Ala-Tyr-d-Lys]-Trp-Met-Phe-NH2
Abbreviated name:99mTc-HYNIC-cyclo-MG1
Agent category:Peptide
Target:Gastrin/cholecystokinin-2 (CCK-2) receptor
Target category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT); planar gamma imaging
Source of signal:99mTc
  • Checkbox In vitro
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Click on protein, nucleotide (RefSeq), and gene for more information about the CCK2 receptor.



The gastrointestinal peptides gastrin and cholecystokinin-2 (CCK2) have various regulatory functions in the brain and gastrointestinal tract (1). Both peptides have the same COOH-terminal pentapeptide amide sequence, GWMDF-NH2, which is the biologically active site (2). Human gastrin is a peptide composed of 33 amino acids and also exists in several C-terminal–truncated forms (3). These truncated forms include minigastrin (MG0), which is a 13-residue peptide with the sequence of d-Glu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2. CCKs exist in a variety of biologically active molecular fragments ranging from 4 to 18 amino acids, including sulphated and unsulphated CCK8, which is an octapeptide (Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe-NH2) (4). Two CCK receptor subtypes have been identified in normal tissues by their binding affinities to gastrin. CCK1 (CCK-A, alimentary) receptors have low affinity for gastrin, and CCK2 (CCK-B, brain) receptors have high affinity for gastrin (4). The sulphated CCK8 peptide displays high affinity for both CCK1 and CCK2 receptors, which are G-protein–coupled (5). These receptors have also been found to be overexpressed in a variety of tumor types (5). CCK2 receptors have been found most frequently in medullary thyroid carcinomas, small-cell lung cancers, astrocytomas, and stromal ovarian cancers (1). CCK1 receptors have been identified in gastroenteropancreatic tumors, meningiomas, and neuroblastomas. Radiolabeled CCK8 peptides have been studied in tumors expressing CCK2 receptors with good specificity for potential in vivo imaging.

A cyclized minigastrin analog, cyclo[γ-d-Glu-Ala-Tyr-d-Lys]-Trp-Met-Phe-NH2 (cyclo-MG1), for the gastrin receptor was N-terminally conjugated with hydrazinonicotinic acid (HYNIC) for radiolabeling with 99mTc and ethylenediamine-N,N’-diacetic acid (EDDA) as a coligand to form 99mTc-HYNIC-cyclo-MG1 (6), which has been evaluated for imaging tumors expressing CCK2 receptors.



Cyclo-MG1 was prepared by solid-phase peptide synthesis (6). The N-terminus was conjugated with a HYNIC-chelating group to produce HYNIC-cyclo-MG1 by N-hydroxysuccinimidyl-HYNIC. HYNIC-MG1 was purified with reverse-phase high-performance liquid chromatography. Radiolabeling was performed by mixing HYNIC-cyclo-MG1 (10-20 µg) with an EDDA/tricine solution, 400 MBq Na99mTcO4, and ZnCl2 (pH 6). The mixture was heated for 30 min at 100°C. The radiochemical purity and specific activity of 99mTc-HYNIC-cyclo-MG1 were >90% and 20–60 TBq/mmol (540–1,620 Ci/mmol), respectively.

In Vitro Studies: Testing in Cells and Tissues


An in vitro receptor-binding assay of 99mTc-HYNIC-cyclo-MG1 was performed on CCK2 receptor–expressing AR42J cells with an affinity constant (Kd) of 19.1 nM (6). Binding of 99mTc-HYNIC-cyclo-MG1 to AR42J cells was 93.5 ± 1.1% of the incubation dose after 120 min at 37°C. 99mTc-HYNIC-cyclo-MG1 exhibited high stability (94–98% intact) in a phosphate-buffered solution containing excess cysteine and human plasma after 24 h of incubation. Log P7.4 of 99mTc-HYNIC-cyclo-MG1 was -3.01.

Animal Studies



Von Guggenberg et al. (6) performed ex vivo biodistribution studies of 99mTc-HYNIC-cyclo-MG1 in nude mice (n = 3/group) bearing R42J tumor xenografts. Each mouse received 1 MBq (27 nCi) 99mTc-HYNIC-cyclo-MG1 by intravenous injection. The tumor radioactivity levels were 3.61 ± 0.40% injected dose per gram (ID/g) at 1 h and 3.40 ± 0.69% ID/g at 4 h. The accumulation of radioactivity in the tumor was blocked by excess human minigastrin to 1.46 ± 0.71% ID/g at 1 h after co-injection. The kidney radioactivity levels (1.92% ID/g at 1 h and 1.95% ID/g at 4 h) were not blocked by human minigastrin. The blood, lung, heart, spleen, pancreas, and liver radioactivity levels were <0.4% ID/g at these two time points. The intestine and stomach radioactivity levels at 1 h were 1.79 ± 0.36 and 1.15 ± 0.39% ID/g, respectively. Accumulation in the intestine and stomach was slightly blocked by human minigastrin to 1.37 ± 0.09 and 0.86 ± 0.32% ID/g, respectively. Little inhibition of radioactivity was observed in the other tissues. The tumor/blood and tumor/muscle ratios were 15 and 36 at 1 h, respectively. The tumor, abdominal area, and kidneys were clearly visualized with single-photon emission computed tomography scintigraphy imaging at 1 h after injection.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


No publication is currently available.

Human Studies


No publication is currently available.


Reubi J.C., Schaer J.C., Waser B. Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors. Cancer Res. 1997;57(7):1377–86. [PubMed: 9102227]
Aly A., Shulkes A., Baldwin G.S. Gastrins, cholecystokinins and gastrointestinal cancer. Biochim Biophys Acta. 2004;1704(1):1–10. [PubMed: 15238241]
Mather S.J., McKenzie A.J., Sosabowski J.K., Morris T.M., Ellison D., Watson S.A. Selection of radiolabeled gastrin analogs for Peptide receptor-targeted radionuclide therapy. J Nucl Med. 2007;48(4):615–22. [PMC free article: PMC2246928] [PubMed: 17401100]
Wang H., Wong P.T., Spiess J., Zhu Y.Z. Cholecystokinin-2 (CCK2) receptor-mediated anxiety-like behaviors in rats. Neurosci Biobehav Rev. 2005;29(8):1361–73. [PubMed: 16120463]
Behr T.M., Behe M.P. Cholecystokinin-B/Gastrin receptor-targeting peptides for staging and therapy of medullary thyroid cancer and other cholecystokinin-B receptor-expressing malignancies. Semin Nucl Med. 2002;32(2):97–109. [PubMed: 11965605]
von Guggenberg E., Sallegger W., Helbok A., Ocak M., King R., Mather S.J., Decristoforo C. Cyclic minigastrin analogues for gastrin receptor scintigraphy with technetium-99m: preclinical evaluation. J Med Chem. 2009;52(15):4786–93. [PubMed: 19591486]


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